WO2000076491A1 - Verwendung eines hochfluorierten oligomeren alkans in der ophthalmologie - Google Patents
Verwendung eines hochfluorierten oligomeren alkans in der ophthalmologie Download PDFInfo
- Publication number
- WO2000076491A1 WO2000076491A1 PCT/EP2000/003817 EP0003817W WO0076491A1 WO 2000076491 A1 WO2000076491 A1 WO 2000076491A1 EP 0003817 W EP0003817 W EP 0003817W WO 0076491 A1 WO0076491 A1 WO 0076491A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ophthalmology
- highly fluorinated
- use according
- alkan
- utilization
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/02—Halogenated hydrocarbons
- A61K31/025—Halogenated hydrocarbons carbocyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
Definitions
- the invention relates to the use of a highly fluorinated oligomeric alkane in ophthalmology according to claim 1.
- US-A-4,490,351 describes the use of liquid perfluorocarbons for treatment and diagnostics in ophthalmology. While such substances are used for the temporary treatment of retinal detachments and as vitreous tamponade, their long-term use, for example as a vitreous replacement, is associated with various types of damage to the eye. Side effects are known, for example of perfluoropolyethers and perfluorocarbons, which are attributed to mechanical damage to the retina and optic nerve, the high density (approx. 1.9 g / cm) of these compounds being held responsible for this.
- DE 44 05 627 AI and EP 05 45 174 AI describe fluorocarbons-containing oligomers of the general formulas (R F ) X -R H where R F is a highly fluorinated alkyl radical which is bonded to the group R H directly or via a link , which represents an alkane radical or hydrogen and x is a number from 1 to 4 and from compounds of the general formula where Y is a hydrogen or a fluorine atom, a is a number from 2 to 16 and b and c - independently of one another are a number between 0 and 1 and d is a number between 0 and 6, with an average degree of oligomerization of 2 to 4.
- the publications mentioned describe the use of the substances described as a lubricant or lubricant and as a ski base and as an oxygen carrier.
- the object is to provide a pharmacological agent for use in ophthalmology which, even when used over a longer period of time, does not cause any or only slight damage to the retina.
- the tissue penetration ability can be described qualitatively by the critical solubility temperature in hexane (abbreviation: CST). This qualitative measure of lipophilia is also a measure of the ability to penetrate the tissue. While in contrast, the low molecular weight R F -RH compounds, as are also known from the prior art mentioned at the outset for use in ophthalmology, generally have CST values below -20 ° C., are the high molecular weight compounds according to the invention Oligomer compounds can only be completely mixed with hexane at temperatures above + 35 ° C and thus document their poor or insolubility in lipids, i.e. their low tissue penetration ability. Surprisingly, they still have a higher solvency for certain non-polar substances than their monomeric analogue.
- the substances according to the invention are not tissue-penetrating because of their special molecular form, despite a very similar chemical composition with the known R F -R H compounds, and are therefore suitable for long-term use in the eye, since it was recognized that the tissue-damaging properties of the known substances depend on their high level Penetration. It is advantageous for ophthalmic applications that the treatment agent used according to the invention does not act mechanically damaging to the eye due to the combination of reduced density and increased viscosity and can therefore be used as a long-term replacement for vitreous bodies.
- the use of the oligomers according to the invention has the advantage that they can also be used in the lower eye segment for a coordinated oxygen therapy for the ischemic retina and, at the same time, an excellent tamponing effect due to the special surface properties and their higher density compared to silicone oil and water .
- the use of the oligomers described according to the invention enables various other ophthalmic applications which were previously reserved exclusively for silicone oils.
- this relates to the use as a volume substitute, e.g. B. in the form of implants.
- completely new ophthalmic applications have also become possible.
- cloudy natural lenses can be replaced. The Extraction of the natural lens to obtain the capsular bag surrounding it, which is followed by an injection of the high-viscosity oligomer into this capsular bag.
- the fluid lens materials enable the accommodation to be maintained.
- oligomers with a high degree of branching can be used for this, or the inherently high viscosity of the oligomers can be further increased by producing gels by adding certain mixtures of water and surface-active substances by known methods.
- the use as an active ingredient carrier is based on the possibility of dissolving pharmacological active ingredients in the oligomers, the unusual combination of solubility on the one hand and suppressed tissue penetration on the other hand being particularly important. Therefore, the use as an active ingredient carrier both in the form of volume substitutes and without this application function is of particular interest.
- a major advantage of the substances described with regard to the use according to the invention is that they have the known properties of fluorocarbons and silicone oil combine, in particular the high viscosity of silicone oil and the high density and oxygen solubility of fluorocarbons, without the known toxicities of other known substances, for example fluorosiloxanes, or the complicated ratios that are present in mixtures of silicone oil and partially fluorinated alkanes and limit or exclude their use as treatment agents in ophthalmology.
- the oligomers offer the advantage in their ophthalmological use that, in contrast to the silicone oils, their removal is achieved by problem-free washing out, since with the perfluorocarbons which have been tried and tested for short-term use in ophthalmic practice, for example perfluorodecalin or perfluorooctane, but also with the partially fluorinated alkanes such as Example C 6 F ⁇ 3 CH 5 or C 4 F 9 C 4 H 9 excellent biocompatible solvents are available. On the other hand, if necessary, an exchange for silicone oil or vice versa can take place without the compounds mixing.
- the oligomeric compounds described have a viscous to highly viscous or even pasty consistency and a density between 1.2 and 1.7 g / cm 3 . They are optically transparent with a refractive index between 1.30 and 1.45. The connections are essentially non-polar. However, as a special feature, compared to the two molecular components alkane and perfluoroalkane, there is a weak characteristic molecular polarity in the isolated state due to the CF -CH 2 grouping typical of the compound.
- the substance-related physical properties such as molecular weight, density, refractive index, viscosity, optical transparency and solubility behavior can be varied depending on the application.
- the physico-chemical properties can also be adjusted by adding perfluorinated or partially fluorinated alkanes.
- the highly fluorinated oligomers are chemically and thermally exceptionally stable and enzymatically non-degradable. They are toxicologically and dermatologically harmless.
- the substances described are prepared and purified in a manner known per se.
- these are prepared as described in DE 41 39 765 or obtained by reacting a branched, perfluorinated olefin with potassium or cesium fluoride in an aprotic solvent with an alkenyl halide and oligomerizing with a radical initiator in a non-polar solvent.
- the purification is carried out, for example, by extractive and column chromatography processes.
- Example 1 The highly fluorinated oligomer (C 6 F ⁇ 3 CH 2 CH) 3 , dissolved in fluorocarbons, is purified on an Al 2 O chromatography column. After removing the solvent, the last traces of volatile impurities are removed in vacuo.
- the highly fluorinated trimer is a uniform and high-purity substance with a molecular weight of 1055.
- the loading with an active ingredient is carried out gently via a solvent which is not miscible with the trimer, after distribution up to the saturation concentration.
- ⁇ -carotene as an active ingredient weakly stains the oligomer.
- the autoclave is sterilized at 121 ° C without changing the physical or chemical properties of the substance.
- the nuclear magnetic data of this substance are as follows:
- the purity of the substance is essentially characterized by the following physical properties: Density: 1.661 g / cm 3 ;
- Viscosity 220 mPas.
- This oligomer is suitable for all uses described above and in the claims and has the advantages mentioned above, in particular in the long-term range.
- Example 2 72 g of tridekafluoro-4,4-dimethylheptene-1 is dissolved in 100 ml of n-hexane and olegomerized with 1.7 g of di-tert-butyl peroxide at 190 ° C. in an autoclave, a reaction mixture resulting from a dimeric and trimeric compound. The mixture is separated by distillation, the trimere being obtained as a viscous colorless oil of the composition [CF 3 CF CF C (CF 3 ) 2 CH 2 CH 2 CH 2 ] 3 with an average molar mass of 1085 daltons.
- the compound corresponds to the general formula of the invention and also confirms a high degree of purity. According to the relevant in vitro tests, the highly fluorinated oil is suitable for the claimed uses.
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT00922666T ATE278396T1 (de) | 1999-06-12 | 2000-04-27 | Verwendung eines hochfluorierten oligomeren alkans in der ophthalmologie |
AU42983/00A AU4298300A (en) | 1999-06-12 | 2000-04-27 | Utilization of a highly fluorinated oligomeric alkan in ophthalmology |
US10/018,398 US7026359B1 (en) | 1999-06-12 | 2000-04-27 | Utilization of a highly fluorinated oligomeric alkane in ophthalmology |
DE50008127T DE50008127D1 (de) | 1999-06-12 | 2000-04-27 | Verwendung eines hochfluorierten oligomeren alkans in der ophthalmologie |
CA2377290A CA2377290C (en) | 1999-06-12 | 2000-04-27 | Utilization of a highly fluorinated oligomeric alkane in ophthalmology |
EP00922666A EP1185256B1 (de) | 1999-06-12 | 2000-04-27 | Verwendung eines hochfluorierten oligomeren alkans in der ophthalmologie |
HK02102747.0A HK1040931B (zh) | 1999-06-12 | 2002-04-11 | 利用一高度氟化齊聚烷於眼科學 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19926890.8 | 1999-06-12 | ||
DE19926890A DE19926890C1 (de) | 1999-06-12 | 1999-06-12 | Verwendung eines hochfluorierten oligomeren Alkans in der Ophthalmologie |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000076491A1 true WO2000076491A1 (de) | 2000-12-21 |
Family
ID=7911063
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2000/003817 WO2000076491A1 (de) | 1999-06-12 | 2000-04-27 | Verwendung eines hochfluorierten oligomeren alkans in der ophthalmologie |
Country Status (10)
Country | Link |
---|---|
US (1) | US7026359B1 (de) |
EP (1) | EP1185256B1 (de) |
CN (1) | CN1322859C (de) |
AT (1) | ATE278396T1 (de) |
AU (1) | AU4298300A (de) |
CA (1) | CA2377290C (de) |
DE (2) | DE19926890C1 (de) |
ES (1) | ES2230093T3 (de) |
HK (1) | HK1040931B (de) |
WO (1) | WO2000076491A1 (de) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
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DE102010010430A1 (de) | 2010-03-05 | 2011-09-08 | Fluoron Gmbh | Füllmaterial für ophthalmologische Implantate |
DE202010003217U1 (de) | 2010-03-05 | 2011-08-04 | Fluoron Gmbh | Füllmaterial für ophthalmologische Implantate |
WO2011113855A2 (en) | 2010-03-17 | 2011-09-22 | Novaliq Gmbh | Pharmaceutical composition for treatment of increased intraocular pressure |
EP2444063A1 (de) | 2010-10-20 | 2012-04-25 | Novaliq GmbH | Flüssige pharmazeutische Zusammensetzungen zur Abgabe von Wirkstoffen |
EP2462921A1 (de) | 2010-11-11 | 2012-06-13 | Novaliq GmbH | Flüssige pharmazeutische Zusammensetzungen zur Behandlung einer Erkrankung der Hinterseite des Auges |
CN103596554A (zh) | 2011-05-25 | 2014-02-19 | 诺瓦利克有限责任公司 | 基于半氟化烷烃类的外用药物组合物 |
DK2806886T3 (en) | 2012-01-23 | 2017-06-06 | Novaliq Gmbh | STABILIZED PROTEIN COMPOSITIONS BASED ON SEMIFLUORED ALKANES |
ES2965828T3 (es) | 2012-09-12 | 2024-04-17 | Novaliq Gmbh | Composiciones de alcano semifluorado |
WO2015011199A1 (en) | 2013-07-23 | 2015-01-29 | Novaliq Gmbh | Stabilized antibody compositions |
EP3355990B1 (de) | 2015-09-30 | 2019-06-12 | Novaliq GmbH | Semifluorierte verbindungen und deren zusammensetzungen |
CN110693825B (zh) | 2015-09-30 | 2022-03-08 | 诺瓦利克有限责任公司 | 用于眼部给药的半氟化化合物 |
WO2017220625A1 (en) | 2016-06-23 | 2017-12-28 | Novaliq Gmbh | Topical administration method |
PL3515420T3 (pl) | 2016-09-22 | 2024-04-08 | Novaliq Gmbh | Kompozycje farmaceutyczne do zastosowania w terapii zapalenia brzegów powiek |
MX2019003364A (es) | 2016-09-23 | 2019-10-02 | Novaliq Gmbh | Composiciones oftalmicas que comprenden ciclosporina. |
EP3612228B1 (de) | 2017-04-21 | 2023-08-23 | Dermaliq Therapeutics, Inc. | Jodzusammensetzungen |
EP3621601A1 (de) | 2017-05-12 | 2020-03-18 | Novaliq GmbH | Pharmazeutische zusammensetzungen mit semifluorierten alkanen zur behandlung von beschwerden im zusammenhang mit kontaktlinsen |
CA3076776A1 (en) | 2017-09-27 | 2019-04-04 | Novaliq Gmbh | Ophthalmic compositions comprising latanoprost for use in the treatment of ocular diseases |
CN111182893A (zh) | 2017-10-04 | 2020-05-19 | 诺瓦利克有限责任公司 | 包含f6h8的眼用组合物 |
EP3758676A1 (de) | 2018-03-02 | 2021-01-06 | Novaliq GmbH | Pharmazeutische zusammensetzungen mit nebivolol |
JP2022502421A (ja) | 2018-10-12 | 2022-01-11 | ノバリック ゲーエムベーハー | 乾性眼疾患の治療のための眼科用組成物 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4490351A (en) * | 1982-03-15 | 1984-12-25 | Children's Hospital Medical Center | Methods of treating disorders of an eye with liquid perfluorocarbons |
EP0563446A1 (de) * | 1992-04-01 | 1993-10-06 | PHARMPUR GmbH | Behandlungsmittel für die Augenheilkunde und seine Verwendung |
DE19536504A1 (de) * | 1995-09-29 | 1997-04-03 | H Prof Dr Meinert | Fluorierte Alkane und ihre Verwendung |
EP0877010A1 (de) * | 1997-05-07 | 1998-11-11 | PHARMPUR GmbH | Fluorierte Alkane und ihre Verwendungen |
DE19861012A1 (de) * | 1998-03-18 | 1999-09-30 | Pharm Pur Gmbh | Behandlungsmittel für die Ophthalmologie |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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DE4139765A1 (de) * | 1991-12-03 | 1993-06-09 | Hoechst Ag, 6230 Frankfurt, De | Oligomere von fluorierten olefinen |
DE4405627A1 (de) * | 1994-02-22 | 1995-08-24 | Hoechst Ag | Fluorkohlenwasserstoffe enthaltende Ölemulsionen |
FR2716678B1 (fr) * | 1994-02-25 | 1996-05-15 | Opsia | Nouveaux composés organiques fluorés, applications en particulier ophtalmologiques et procédé de fabrication. |
-
1999
- 1999-06-12 DE DE19926890A patent/DE19926890C1/de not_active Expired - Lifetime
-
2000
- 2000-04-27 WO PCT/EP2000/003817 patent/WO2000076491A1/de active IP Right Grant
- 2000-04-27 EP EP00922666A patent/EP1185256B1/de not_active Expired - Lifetime
- 2000-04-27 ES ES00922666T patent/ES2230093T3/es not_active Expired - Lifetime
- 2000-04-27 AT AT00922666T patent/ATE278396T1/de not_active IP Right Cessation
- 2000-04-27 CA CA2377290A patent/CA2377290C/en not_active Expired - Lifetime
- 2000-04-27 US US10/018,398 patent/US7026359B1/en not_active Expired - Fee Related
- 2000-04-27 CN CNB008116326A patent/CN1322859C/zh not_active Expired - Lifetime
- 2000-04-27 DE DE50008127T patent/DE50008127D1/de not_active Expired - Lifetime
- 2000-04-27 AU AU42983/00A patent/AU4298300A/en not_active Abandoned
-
2002
- 2002-04-11 HK HK02102747.0A patent/HK1040931B/zh not_active IP Right Cessation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4490351A (en) * | 1982-03-15 | 1984-12-25 | Children's Hospital Medical Center | Methods of treating disorders of an eye with liquid perfluorocarbons |
EP0563446A1 (de) * | 1992-04-01 | 1993-10-06 | PHARMPUR GmbH | Behandlungsmittel für die Augenheilkunde und seine Verwendung |
DE19536504A1 (de) * | 1995-09-29 | 1997-04-03 | H Prof Dr Meinert | Fluorierte Alkane und ihre Verwendung |
EP0877010A1 (de) * | 1997-05-07 | 1998-11-11 | PHARMPUR GmbH | Fluorierte Alkane und ihre Verwendungen |
DE19861012A1 (de) * | 1998-03-18 | 1999-09-30 | Pharm Pur Gmbh | Behandlungsmittel für die Ophthalmologie |
Non-Patent Citations (3)
Title |
---|
HOERAUF H ET AL: "[O44--a solvent for silicone oil adhesions on intraocular lenses]. O44--ein Losungsmittel fur Silikonoladhasionen auf Intraokularlinsen.", KLINISCHE MONATSBLATTER FUR AUGENHEILKUNDE, (1999 FEB) 214 (2) 71-6., XP000956155 * |
KOBUCH, K. A. (1) ET AL: "A new hydrofluorocarbon with increased viscosity and reduced density for long-term tamponade of the lower retina.", IOVS, (MARCH 15, 2000) VOL. 41, NO. 4, PP. S662. MEETING INFO.: ANNUAL MEETING OF THE ASSOCIATION IN VISION AND OPTHALMOLOGY. FORT LAUDERLADE, FLORIDA, USA APRIL 30-MAY 05, 2000 ASSOCIATION FOR RESEARCH IN VISION AND OPHTHALMOLOGY., XP000956167 * |
SANTORO, E. ET AL: "Mass spectra of some partially fluorinated aliphatic compounds", ORG. MASS SPECTROM. (1973), 7(2), 123-31, 1973, XP002150832 * |
Also Published As
Publication number | Publication date |
---|---|
HK1040931A1 (en) | 2002-06-28 |
CA2377290C (en) | 2010-07-20 |
HK1040931B (zh) | 2005-02-25 |
EP1185256B1 (de) | 2004-10-06 |
AU4298300A (en) | 2001-01-02 |
DE50008127D1 (de) | 2004-11-11 |
CA2377290A1 (en) | 2000-12-21 |
CN1374860A (zh) | 2002-10-16 |
DE19926890C1 (de) | 2000-07-27 |
ES2230093T3 (es) | 2005-05-01 |
ATE278396T1 (de) | 2004-10-15 |
EP1185256A1 (de) | 2002-03-13 |
CN1322859C (zh) | 2007-06-27 |
US7026359B1 (en) | 2006-04-11 |
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